The cloning of at least fourteen subtypes of P2 nucleotide receptors has presented a unique challenge to medicinal chemists: the design of selective agonists and antagonists for this multiplicity of receptors with few existing leads. These receptors regulate function of the central nervous system, the immune system, the cardiovascular system, and smooth muscles. Our laboratory is developing selective agonists and antagonists for these receptors, for use both as pharmcological tools for probing receptor function and as potential therapeutic agents. P2X receptors are ligand-gated ion channels. P2Y receptors are G protein coupled receptors linked to the phosphatidyl inositol pathway as second messenger. The human P2Y1 receptor as representative of the P2Y family of metabotropic purine and pyrimidine nucleotide receptors may be modeled based on a rhodopsin template, and the resulting model is highly consistent with pharmacological and mutagenesis results. Charged residues in both the transmembrane and extracellular domains and two disulfide bridges essential for receptor activation have been identified. Selective P2Y1 receptor antagonists such as the adenine nucleotide MRS 2179 (N-methyl-2'-deoxyadenosine-3',5'-bisphosphate) and it carbocyclic analogue are under development. Modeling of P2X receptors has not been achieved, since no template for the extracellular nucleotide binding region exists. Nevertheless, a selective antagonist, MRS 2220, and a potentiator, MRS 2219, of this subtype have been identified. Both are based structurally on pyridoxal-5'-phosphate antagonists (such as PPADS), for which the SAR is being examined at all of the P2 receptor subtypes. We have also synthesized nucleotides containing conformationally constrained ribose-like rings, in order to freeze a conformation that provides favorable affinity and/or selectivity at P2 receptors.